A recent theory indicated that the cause of bipolar disorder related to abnormal serotonin chemistry in the brain. Imaging of serotonin transporters is of great value in studies of correlation between changes of the serotonergic system and other mental disorders, and in evaluation of the effects of the antidepressants and monitoring the progress. In order to improve the quality of diagnosis and treatment of individuals with mental disorders, the radiotracer for imaging serotonin transporter has a great potential in clinical use.
Hank Kung, PhD, professor at the University of Pennsylvania has dedicated to develop new serotonin transporter imaging agents and ever mentioned a potential serotonin transporter imaging agent-ADAM in following two papers-“2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM): an improved serotonin transporter ligand” Nucl. Med. Biol. 2000, 27, 249-254 and “Quantification of Serotonin Transporters in Nonhuman Primates Using [123I]ADAM and SPECT”, J. Nucl. Med. 2001, 42, 1556-1562. According to his studies, it has been proved that ADAM has a potential in clinical applications.
However, there are still technical bottlenecks during the synthesis process of ADAM. Refer to FIG. 1, during the synthesis process of N,N-dimethyl-2-[(4-bromo-2-nitrophenyl)thio]-dimethylamine (compound 4), nitro groups and amides of the reactant N,N-Dimethyl-2[(4-bromo-2-nitrophenyl)thio]-benzamide (compound 2) are reduced into amino groups. The problem of low yield rate often occurs. This is due to water molecule generated during reduction of the nitro group into the amino group. Sometimes the anhydrous-form blue-colored cobaltous chloride (CoCl2) is unable to remove all water molecules in the synthesis system and this causes incomplete reduction of the nitro group. On the other hand, water molecule may react with borane (BH3) so that the reduction efficiency is decreased. Thus the reduction efficiency of the amide is further affected.
Even using 10 equivalents of borane and adding 1.5 equivalents of anhydrous cobalt chloride, not all nitro groups and amides are reduced easily and completely. A mixture of compound 2, compound 3, compound 3A and compound 4 shown in FIG. 2D in different ratios is obtained. The adds complexity and inconvenience in isolation of purification of the compounds. Although Dr. Kung did not add cobalt chloride in this step, the side reactions along with the nitro groups being reduced into the amino groups are still not avoided. After purification, the yield rate of compound 3A produced by the Dr. Kung's method is 80%. This affects the yield rate of the final product SnADAM.
Moreover, during the synthesis of ADAM, the substitution reaction between the compound 4 and bis(tri-n-butyltin) is catalyzed by a zero-valent palladium complex-Tetrakis(triphenylphosphine)palladium(Pd[P(C6H5)3]4). The reaction is refluxed for 96 hours to get the final product SnADAM (compound 5). For improvement in synthesis processes to achieve industrialization, the production time should be shortened significantly.
Thus there is room for improvement and a need to provide a novel synthesis method for rapid and high-yield production of radiotracer precursor SnADAM.